Abstract
The secretion of glucocorticoids in mammals is under circadian control, but glucocorticoids themselves are also implicated in modulating circadian clock gene expression. We have shown that the expression of the circadian clock protein PER1 in the forebrain is modulated by stress, and that this effect is associated with changes in plasma corticosterone levels, suggesting a possible role for glucocorticoids in the mediation of stress-induced changes in the expression of PER1 in the brain. To study this, we assessed the effects of adrenalectomy and of pretreatment with the glucocorticoid receptor antagonist, mifepristone, on the expression of PER1 in select limbic and hypothalamic regions following acute exposure to a neurogenic stressor, restraint, or a systemic stressor, 2-Deoxy-D-glucose (2DG) in rats. Acute restraint suppressed PER1 expression in the oval nucleus of the bed nucleus of the stria terminalis (BNSTov) and the central nucleus of the amygdala (CEAl), whereas 2DG increased PER1 in both regions. Both stressors increased PER1 expression in the paraventricular (PVN) and dorsomedial (DMH) nuclei of the hypothalamus, and the piriform cortex (Pi). Adrenalectomy and pretreatment with mifepristone reversed the effects of both stressors on PER1 expression in the BNSTov and CEAl, and blocked their effects in the DMH. In contrast, both treatments enhanced the effects of restraint and 2DG on PER1 levels in the PVN. Stress-induced PER1 expression in the Pi was unaffected by either treatment. PER1 expression in the suprachiasmatic nucleus, the master circadian clock, was not altered by either exposure to stress or by the glucocorticoid manipulations. Together, the results demonstrate a key role for glucocorticoid signaling in stress-induced changes in PER1 expression in the brain.
Highlights
The circadian clock drives daily rhythms in behavior and physiology and these rhythms help animals adapt to their cyclic environment
We have shown that depletion of endogenous glucocorticoids via adrenalectomy (ADX) or selective genetic deletion of brain glucocorticoid receptors (GR), blunt the rhythm of expression of the clock protein, PER2 in nuclei of the central extended amygdala, the oval nucleus of the bed nucleus of the stria terminalis (BNSTov) and the lateral part of the central nucleus of the amygdala (CEAl), without affecting the rhythms of the suprachiasmatic nucleus (SCN) in rats [13,14,15,16]
In the present study we found, that depletion of endogenous glucocorticoids via ADX or treatment with the GR blocker, mifepristone altered the changes in PER1 expression induced by a neurogenic stressor, restraint, or by a systemic stressor, 2DG
Summary
The circadian clock drives daily rhythms in behavior and physiology and these rhythms help animals adapt to their cyclic environment. Glucocorticoids and Stress-Induced PER1 coordination of the master clock in the suprachiasmatic nucleus (SCN) with subordinate circadian clocks elsewhere in the brain and in the periphery [1, 2]. This coordination is sensitive to a range of external and systemic stressful conditions that disrupt homeostasis, leading to dysregulation of circadian physiological and behavioral rhythms [3,4,5]. We have shown that depletion of endogenous glucocorticoids via adrenalectomy (ADX) or selective genetic deletion of brain glucocorticoid receptors (GR), blunt the rhythm of expression of the clock protein, PER2 in nuclei of the central extended amygdala, the oval nucleus of the bed nucleus of the stria terminalis (BNSTov) and the lateral part of the central nucleus of the amygdala (CEAl), without affecting the rhythms of the SCN in rats [13,14,15,16]
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